Abstract
The majority of human cancer shows chromosomal instability (CIN). Although the precise mechanism remains largely uncertain, proper progression of mitosis is crucial. B-type lamins were suggested to be components of the spindle matrix of mitotic cells and to be involved in mitotic spindle assembly; thus, B-type lamins may contribute to the maintenance of chromosome integrity. Here, using a proteomic approach, we identified lamin B2 as a novel protein involved in CIN. Lamin B2 expression decreased in colorectal cancer cell lines exhibiting CIN, as compared with colorectal cancer cell lines exhibiting microsatellite instability (MIN), which is mutually exclusive to CIN. Importantly, lamin B2 knockdown in MIN-type colorectal cancer cells induced CIN phenotypes such as aneuploidy, chromosome mis-segregation and aberrant spindle assembly, whereas ectopic expression of lamin B2 in CIN-type colorectal cancer cells prevented their CIN phenotypes. Additionally, immunohistochemical analysis showed a lower expression of lamin B2 in cancer tissues extracted from patients with sporadic colorectal cancer (CIN-type) than that from patients with hereditary non-polyposis colorectal cancer (HNPCC; MIN type). Intriguingly, mitotic lamin B2 in MIN cancer cells was localized outside the spindle poles and mitotic lamin B2 localization was diminished in CIN cancer cells, suggesting an important role of lamin B2 in proper mitotic spindle formation. The obtained results suggest that lamin B2 maintains chromosome integrity by ensuring proper spindle assembly and that its downregulation causes CIN in colorectal cancer.
Highlights
Cancer is widely accepted as a disease of genetic instability
Proteomic analysis of colorectal cancer cell lines reveals that lamin B2 is downregulated in chromosomal instability (CIN) cell lines chromosome integrity
To search for the factors involved in CIN, we compared protein expression profiles of CIN and microsatellite instability (MIN) colorectal cancer cell lines by a proteomic approach
Summary
Cancer is widely accepted as a disease of genetic instability. This instability exists as two distinct forms: chromosomal instability (CIN), characterized by gains or losses of whole or large portions of chromosomes, and microsatellite instability (MIN), characterized by mutations at the nucleotide level.[1,2,3] The fact that most cancers have abnormal chromosomal content, called aneuploidy, indicates that CIN has an important role in carcinogenesis.[4]CIN has been recognized to occur as a result of chromosome mis-segregation, which is caused by defects in mitotic functions, such as chromosome condensation, sister-chromatid cohesion, kinetochore structure, centrosome formation and microtubule dynamics, as well as the mitotic checkpoint that monitors the proper progression of mitosis.[4]. Cancer is widely accepted as a disease of genetic instability. This instability exists as two distinct forms: chromosomal instability (CIN), characterized by gains or losses of whole or large portions of chromosomes, and microsatellite instability (MIN), characterized by mutations at the nucleotide level.[1,2,3] The fact that most cancers have abnormal chromosomal content, called aneuploidy, indicates that CIN has an important role in carcinogenesis.[4]. Several proteins involved in mitotic processes have been shown to have mutated or altered expression levels in cancer.[5,6,7,8] we previously showed that core kinetochore proteins, CENP-A and CENP-H, are overexpressed in colorectal cancer and involved in CIN,[9,10,11] suggesting that nuclear proteins are responsible for chromosome integrity
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